The RNA-binding protein HuR promotes nonalcoholic steatohepatitis (NASH) progression by enhancing death signaling pathway

Li, X.; Yuan, B.; Yao, Z.; Sun, X.; Guo, W.; Chen, Z.

doi:10.1101/2020.10.21.348185

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bioRxiv · 10.1101/2020.10.21.348185

The RNA-binding protein HuR promotes nonalcoholic steatohepatitis (NASH) progression by enhancing death signaling pathway

Li, X.·Yuan, B.·Yao, Z.·Sun, X.·Guo, W.·Chen, Z.

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Abstract

Hepatocyte death triggers liver inflammation, liver injury, and fibrosis, which contributes to non-alcoholic steatohepatitis (NASH) pathogenesis. However, whether RNA processing regulates death signaling pathway during NASH progression is not investigated. In this study, we show that HuR, a widely expressed RNA-binding protein, promotes NASH progression by increasing DR5/caspase8/caspase3-mediated hepatocyte death. Cytosolic HuR levels are abnormally elevated in human patients with NASH. Hepatocyte-specific deletion of HuR protects against MCD-induced NASH by decreasing liver steatosis, inflammation and cell death, whereas hepatic overexpression of HuR induces liver injury by increasing DR5-induced hepatocyte death. Furthermore, in primary hepatocytes, HuR deficiency ameliorates PA&TNF-induced hepatocyte death due to decreased DR5/caspase8/caspase 3 signaling pathway while overexpression of HuR induces hepatocyte death by increasing DR5/caspase8/caspase 3 signaling pathway. Mechanistically, HuR directly binds to 3'-UTR of DR5 transcript and promotes its mRNA stability, contributing to the hepatocyte death during NASH progression. Our data reveal a novel mechanism by which HuR promotes mRNA stability of DR5, which contributes to NASH progression.

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Li, X., Yuan, B., Yao, Z., Sun, X., Guo, W., Chen, Z.. 2020-10-21. The RNA-binding protein HuR promotes nonalcoholic steatohepatitis (NASH) progression by enhancing death signaling pathway. https://doi.org/10.1101/2020.10.21.348185

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